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Mol Oncol. 2014 Mar;8(2):297-310. doi: 10.1016/j.molonc.2013.12.001. Epub 2013 Dec 12.

Transfection of chimeric anti-CD138 gene enhances natural killer cell activation and killing of multiple myeloma cells.

Author information

1
Department of Hematology, The Myeloma and Lymphoma Center, Changzheng Hospital, The Second Military Medical University, 415 Fengyang Rd, Shanghai 200003, China.
2
Institute of Biotechnology and Clinical Immunology, Research Laboratory of Jiangsu Province, Soochow University, Suzhou 215007, China.
3
Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong Special Administrative Region.
4
Department of Lymphoma/Myeloma, Division of Cancer Medicine, and Center for Cancer Immunology Research, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
5
Department of Hematology, The Myeloma and Lymphoma Center, Changzheng Hospital, The Second Military Medical University, 415 Fengyang Rd, Shanghai 200003, China. Electronic address: houjian167@sohu.com.

Abstract

Reprogramming of NK cells with a chimeric antigen receptor (CAR) proved an effective strategy to increase NK cell reactivity and recognition specificity toward tumor cells. To enhance the cytotoxicity of NK cells against CD138-positive multiple myeloma (MM) cells, we generated genetically modified NK-92MI cells carrying a CAR that consists of an anti-CD138 single-chain variable fragment (scFv) fused to the CD3ζ chain as a signaling moiety. The genetic modification through a lentiviral vector did not affect the intrinsic cytolytic activity of NK-92MI toward human erythroleukemic cell line K562 cells or CD138-negative targets. However, these retargeted NK-92MI (NK-92MI-scFv) displayed markedly enhanced cytotoxicity against CD138-positive human MM cell lines (RPMI8226, U266 and NCI-H929) and primary MM cells at various effector-to-target ratios (E:T) as compared to the empty vector-transfected NK-92MI (NK-92MI-mock). In line with the enhanced cytotoxicity of NK-92MI-scFv, significant elevations in the secretion of granzyme B, interferon-γ and proportion of CD107a expression were also found in NK-92MI-scFv in response to CD138-positive targets compared with NK-92MI-mock. Most importantly, the enhancement in the cytotoxicity of NK-92MI-scFv did not attenuate with 10Gy-irradiation that sufficiently blocked cell proliferation. Moreover, the irradiated NK-92MI-scFv exerted definitely intensified anti-tumor activity toward CD138-positive MM cells than NK-92MI-mock in the xenograft NOD-SCID mouse model. This study provides the rationale and feasibility for adoptive immunotherapy with CD138-specific CAR-modified NK cells in CD138-positive plasmacytic malignancies, which potentially further improves remission quality and prolongs the remission duration of patients with MM after upfront chemotherapy.

KEYWORDS:

Adoptive immunotherapy; CD138 (syndecan-1); Chimeric antigen receptor; Multiple myeloma; NK cells

PMID:
24388357
PMCID:
PMC5528539
DOI:
10.1016/j.molonc.2013.12.001
[Indexed for MEDLINE]
Free PMC Article

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